Large granular T-cell leukemia is a clonal hematological condition often associated with autoimmune disorders. Whether small-sized T-cell clones that are otherwise asymptomatic can promote immune ...kidney disorders remains elusive. In this monocentric retrospective cohort in a tertiary referral center in France, we reviewed characteristics of 29 patients with T-cell clone proliferation and autoimmune kidney disorders. Next-generation sequencing of the T-cell receptor of circulating T-cells was performed in a subset of patients. The T-cell clones were detected owing to systematic screening (mean count 0.32 × 10
/L, range 0.13-3.7). Strikingly, a common phenotype of acute interstitial nephropathy was observed in 22 patients (median estimated glomerular filtration rate at presentation of 22 mL/min/1.73 m
(range 0-56)). Kidney biopsies showed polymorphic inflammatory cell infiltration (predominantly CD3
T-cells, most of them demonstrating positive phospho-
staining) and non-necrotic granuloma in six cases. Immune-mediated glomerulopathy only or in combination with acute interstitial nephropathy was identified in eight patients. Next-generation sequencing (
= 13) identified a major T-cell clone representing more than 1% of the T-cell population in all but two patients. None had a mutation of
. Twenty patients (69%) had two or more extra-kidney autoimmune diseases. Acute interstitial nephropathies were controlled with corticosteroids, cyclosporin A, or tofacitinib. Thus, we showed that small-sized T-cell clones (i.e., without lymphocytosis) undetectable without specific screening are associated with various immune kidney disorders, including a previously unrecognized phenotype characterized by severe inflammatory kidney fibrosis and lymphocytic JAK/STAT activation.
Antibody-mediated rejection is a main cause of long-term kidney allograft loss. Nonad-herence and tacrolimus intrapatient variability have been identified as risk factors for developing de novo ...donor-specific antibodies. Tacrolimus, given once daily, can improve adherence and reduce variabilities among patients. The aim of this retrospective observational study was to compare the incidences of donor-specific antibodies at 2 years posttransplant in de novo kidney transplant recipients given tacrolimus either once or twice daily.
Non-HLA sensitized de novo kidney-transplant recipients given tacrolimus either once daily (n = 82) or twice daily (n = 168), combined with mycophenolic acid with or without steroids, were included in the study. All patients were screened for anti-HLA antibodies before transplant, at 6, 12, and 24 months posttransplant, and each time the patient presented with impaired kidney function.
The 2-year incidence of donor-specific antibodies was 2.8%. During the follow-up period, 6 patients (3.6%) receiving tacrolimus twice daily and one patient (1.2%) receiving tacrolimus once daily developed a donor-specific antibody (P = .43). The incidence of antibody-mediated rejection was 4.8% under tacrolimus once daily and 2.7% under tacrolimus twice daily (P = .5). Tacrolimus intrapatient variability was similar with both formulations and was not associated with development of donor-specific antibodies.
The use of tacrolimus-based immunosup-pression associated with mycophenolic acid was associated with a low risk of de novo donor-specific antibodies. After 2 years, the incidence of de novo donor-specific antibodies did not differ significantly between patients treated with tacrolimus once daily versus those treated with the twice-daily formulation.
Keywords: Aging; Kidney; CCR2; Macrophages; CD73; Mesenchymal stromal cells; Senescence; Inflammaging The incidence of disorders associated with low inflammatory state, such as chronic kidney ...disease, increases in the elderly. The accumulation of senescent cells during aging and the senescence-associated secretory phenotype, which leads to inflammaging, is known to be deleterious and account for progressive organ dysfunction. To date, the cellular actors implicated in chronic inflammation in the kidney during aging are still not well characterized. Using the DECyt method, based on hierarchical clustering of flow cytometry data, we showed that aging was associated with significant changes in stromal cell diversity in the kidney. In particular, we identified two cell populations up-regulated with aging, the mesenchymal stromal cell subset (kMSC) expressing CD73 and the monocyte-derived Ly6C.sup.+CCR2.sup.+macrophage subset expressing pro-inflammatory cytokines. Aged CD73.sup.+kMSCs depicted senescence associated features with low proliferation rate, increased DNA damage foci and Ccl2 expression. Using co-cultures experiments, we showed that aged CD73.sup.+kMSC promoted monocyte activation and secretion of inflammatory cytokines albeit less efficiently than young CD73.sup.+kMSCs. In the context of ageing, increased frequency of CD73.sup.+ kMSC subpopulations could provide additional niche factors to newly recruited monocytes favoring a positive regulatory loop in response to local inflammation. Interfering with such partnership during aging could be a valuable approach to regulate kidney inflammaging and to limit the risk of developing chronic kidney disease in the elderly. Author Affiliation: (1) Institute of Metabolic and Cardiovascular Diseases, UMR1048, BP 84225, 1 av Jean Pouhles, 31432, Toulouse, Cedex 4, France (2) Paul Sabatier University, 31062, Toulouse, Cedex 9, France (3) Rangueil Hospital, CHU, 31059, Toulouse, Cedex 9, France (n) angelo.parini@inserm.fr (p) victorine.douin@inserm.fr Article History: Registration Date: 11/19/2020 Received Date: 07/24/2020 Accepted Date: 11/19/2020 Online Date: 12/12/2020 Byline:
Abstract
Background
In the era of prophylaxis, Pneumocystis pneumonia (PCP) has become a late-onset opportunistic infection requiring indications for prolonged prophylaxis to be defined. The primary ...objective of our study was therefore to evaluate risk factors associated with late-onset PCP. The secondary objective was to assess the impact of this infection on graft and patient survival.
Methods
We conducted a French case-control study in Bordeaux and Toulouse center by matching 1 case to 1–2 controls from the same center based on the transplant date and the type of induction treatment.
Results
Seventy cases and 134 controls were included. PCP occurred at a median of 3 years after transplantation. The total lymphocyte count and CD4+ and CD8+ T-lymphocyte values were lower in the cases than in their matched controls on the day of infection and annually up to 4 years earlier. The covariables independently associated with PCP were the total lymphocyte count 1 year before Pneumocystis, mTOR inhibitors used as maintenance immunosuppressive drugs, and the administration of corticosteroid boluses used in acute rejection. A total lymphocyte count threshold <1000/µL offered the best predictive value for infection occurrence. PCP was associated with high incidence of graft loss and patient death (30% and 17% respectively, 3 years after PCP).
Conclusions
Pneumocystis pneumonia has dramatic consequences in kidney transplant recipients; a targeted prophylaxis based on simple criteria, such as chronic lymphopenia and/or history of corticosteroid boluses, could be useful to avoid life-threatening complications.
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