The impact of corticosteroid withdrawal on medium-term graft histological changes in kidney transplant (KT) recipients under standard immunosuppression is uncertain. As part of an open-label, multicenter, prospective, phase IV, 24-month clinical trial (ClinicalTrials.gov, NCT02284464) in low-immunological-risk KT recipients, 105 patients were randomized, after a protocol-biopsy at 3 months, to corticosteroid continuation (CSC, n = 52) or corticosteroid withdrawal (CSW, n = 53). Both groups received tacrolimus and MMF and had another protocol-biopsy at 24 months. The acute rejection rate, including subclinical inflammation (SCI), was comparable between groups (21.2 vs. 24.5%). No patients developed dnDSA. Inflammatory and chronicity scores increased from 3 to 24 months in patients with, at baseline, no inflammation (NI) or SCI, regardless of treatment. CSW patients with SCI at 3 months had a significantly increased chronicity score at 24 months. HbA1c levels were lower in CSW patients (6.4 ± 1.2 vs. 5.7 ± 0.6%; p = 0.013) at 24 months, as was systolic blood pressure (134.2 ± 14.9 vs. 125.7 ± 15.3 mmHg; p = 0.016). Allograft function was comparable between groups and no patients died or lost their graft. An increase in chronicity scores at 2-years post-transplantation was observed in low-immunological-risk KT recipients with initial NI or SCI, but CSW may accelerate chronicity changes, especially in patients with early SCI. This strategy did, however, improve the cardiovascular profiles of patients.

The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.

BACKGROUND & AIMS:

The incidence and outcomes of coronavirus disease 2019 (COVID-19) in immunocompromised patients are a matter of debate.

METHODS:

We performed a prospective nationwide study including a consecutive cohort of liver transplant patients with COVID-19 recruited during the Spanish outbreak from 28 February to 7 April, 2020. The primary outcome was severe COVID-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardised incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe COVID-19 among hospitalised patients were analysed using multivariate Cox regression.

RESULTS:

A total of 111 liver transplant patients were diagnosed with COVID-19 (SIR = 191.2 [95% CI 190.3-192.2]). The epidemiological curve and geographic distribution overlapped widely between the liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. A total of 12 patients were admitted to the ICU (10.8%). The mortality rate was 18%, which was lower than in the matched general population (SMR = 95.5 [95% CI 94.2-96.8]). Overall, 35 patients (31.5%) met criteria of severe COVID-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19 (relative risk = 3.94; 95% CI 1.59-9.74; p = 0.003), particularly at doses higher than 1,000 mg/day (p = 0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit.

CONCLUSIONS:

Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring COVID-19 but their mortality rates are lower than the matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe COVID-19. However, complete immunosuppression withdrawal should be discouraged.

LAY SUMMARY:

In liver transplant patients, chronic immunosuppression increases the risk of acquiring COVID-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalised patients.

American Transplant Congress, 30 May- 3 June 2020, Pennsylvania, USA

TTS 2018. 27th International Congress of The Transplantation Society. June 30-July 5 Madrid, Spain. Introduction Steroids represent a mainstay of immunosuppression after kidney transplant. The infiltration into the graft of active T cells following KT depends on the expression of chemokines and their interaction with their T-cell receptors. However, the natural history of the expression of these molecules in patients who undergo steroid withdrawal after transplant is unknown. Materials and Methods In a controlled clinical trial (NCT02284464), a total of 176 KT patients with low immunological risk were recruited to randomly receive either conventional triple immunosuppression: steroids, TAC and MMF (Group A) versus steroid withdrawal at the 3 post-KT month (Group B). We compared the evolution of CCR4highCD4+ and CXCR3highCD4+ lymphocyte subpopulations in graft blood (GB) extracted by fine needle aspiration puncture determined by flow cytometry in patients after steroid withdrawal at the 3 month post-KT versus patients who continue to receive conventional triple immunosuppression. Measurements were made at 3 (baseline) and 6 months post-KT in GB and in peripheral blood (PB). Results So far, 68 patients have been randomized (34 in each group). There were no significant differences in the clinical and demographic characteristics between the groups at baseline. The first analysis (at 3 months) in those patients who had completed 6 months of follow-up (Group A: n=13; Group B: n=15) showed a significant increase in the CCR4highCD4 subpopulations in GB versus PB in both groups. However, at six months a significant increase in GB versus PB was only seen in Group A. There were no significant differences in the CXCR3highCD4+ lymphocyte subpopulation at the third or sixth month between GB and PB in either group (Table). JOURNAL/trans/04.02/00007890-201807001-00969/table1-969/v/2018-08-28T120805Z/r/image-tiff Conclusion These preliminary results could suggest a possible effect of prednisone that would favor the recruitment of CCR4highCD4+ cells into the renal graft. Spanish Ministry of Economy and Competitiveness (MINECO) (grant ICI14/00016) from the Instituto de Salud Carlos III co-funded by the Fondo Europeo de Desarrollo Regional–FEDER, RETICS (REDINREN RD12/0021/0015, RD16/0009/0006). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

TTS 2018. 27th International Congress of The Transplantation Society. June 30-July 5 Madrid, Spain. Introduction Steroids represent one of the mainstays of immunosuppression after kidney transplant (KT). Steroid withdrawal reduces metabolic and cardiovascular complications, but whether it increases the risk of acute rejection and the generation of donor-specific anti-HLA antibodies (DSA) is currently undetermined. Materials and Methods In a controlled clinical trial (NCT02284464), a total of 176 KT patients with low immunological risk were recruited to randomly receive either conventional triple immunosuppression: steroids, TAC and MMF versus steroid withdrawal at the third post-KT month. We compared the incidence of de novo DSA, determined by Luminex Mixed and Luminex Single Antigen (One Lambda®), and its impact on graft histology in patients with steroid withdrawal at the 3 post-KT month (after a protocol biopsy) versus patients who continue to receive conventional triple immunosuppression. Results So far, 68 patients have been randomized (34 per group), with no significant differences in the clinical and demographic characteristics between the groups. The intermediate analysis in those patients who had completed one year of follow-up (n=28) showed no significant differences in the formation of DSA (0% vs. 0%), nor was there rejection in those patients in whom prednisone was withdrawn after randomization. Patients with triple therapy showed a trend toward better renal function compared to those without steroids at the first post-KT year (1.29±0.25 vs. 1.56±0.42 mg/dL, P=0.088). HbA1c levels were similar between both group at the first post-KT year (5.79±0.59 vs. 5.68±0.81%, P=0.734). Conclusion The preliminary results show that steroid withdrawal at the 3 month post-KT seems safe when assessing the appearance of rejection and formation of DSA compared to the patients who continued to receive conventional triple immunosuppression. Spanish Ministry of Economy and Competitiveness (MINECO) (grant ICI14/00016) from the Instituto de Salud Carlos III co-funded by the Fondo Europeo de Desarrollo Regional–FEDER, RETICS (REDINREN RD12/0021/0015, RD16/0009/0006, RD16/0009/0003, RD16/0009/0030, RD16/0009/0031). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

TTS 2018. 27th International Congress of The Transplantation Society. June 30-July 5 Madrid, Spain. Introduction Monocytes comprise a heterogeneous population divided according to the membrane expression level of their molecules. One of these populations is the CD14++CD16+, which presents proinflammatory characteristics. Our aim was to evaluate the role of this monocyte population in renal transplant recipients with borderline rejection. Material and Methods This controlled clinical trial (NCT02284464) recruited patients with a low immunological risk to randomly receive conventional triple therapy (steroids, TAC and MMF) versus steroid withdrawal three months after the protocol biopsy. We analysed 66 patients with either a normal histology or borderline rejection. In all the patients we studied pre-randomisation levels of CD14++CD16+ at the third month in peripheral blood (PB) and blood extracted from the graft by fine needle aspiration cytology (FNAP). The monocytes were analysed by flow cytometry using CD14 and CD16 monoclonal antibodies. Results Of the 66 patients, 38 (51.1±12.8 years; 68.4% men) had a normal biopsy and 28 (57.8±9.5 years; 67.9% men) had borderline rejection. The percentage of proinflammatory monocytes was similar in the PB and FNAP samples from the patients with a normal biopsy (PB: 13.2±12.9 vs FNAP:16.3±14.3%; p=0.070). However, in the group with borderline rejection the difference in the percentage of these monocytes was significantly greater in the FNAP sample compared to the PB sample (PB: 7.9±5.4 vs FNAP: 16.9±16.5%; p=0.006). No differences were seen at the time of biopsy in renal function or proteinuria (Normal: Cr=1.6±0.6 vs Borderline: 1.7±0.5 mg/dL; p=0.536 and Normal: 268.2±197.9 vs Borderline: 269.3±239.8 mg/24h; p=0.986). Conclusion These preliminary results show that patients with a diagnosis of borderline rejection in the protocol biopsy present a significant difference in CD14++CD16+ monocytes between peripheral blood and graft blood, despite having a stable renal function. This suggests recruitment of these proinflammatory monocytes. Spanish Ministry of Economy and Competitiveness (MINECO) (grant ICI14/00016) from the Instituto de Salud Carlos III co-funded by the Fondo Europeo de Desarrollo Regional-FEDER, RETICS (REDINREN RD16/0009/0006). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

18th Congress of the European Society for Organ Transplantation, 24-27 September 2017, Barcelona, Spain

18th Congress of the European Society for Organ Transplantation, 24-27 September 2017, Barcelona, Spain