Spectrum of Kidney Disorders Associated with T-Cell Immunoclones

Abstract

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 × 109/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 m2 (range 0–56)). Kidney biopsies showed polymorphic inflammatory cell infiltration (predominantly CD3+ T-cells, most of them demonstrating positive phospho-STAT3 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 (n = 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 STAT3. 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.

Sepsis Unveils T-cell Large Granular Lymphocytic Leukemia in the Setting of End-Stage Renal Disease: A Rare Hematologic Malignancy

“…Leukemia, traditionally perceived as one of the most prevalent and manageable cancers with favorable prognoses, assumes a chronic and asymptomatic course when categorized as a subtype of LGL leukemia. Demographic studies conducted in Europe and America estimate the average incidence of this rare cancer to be between 0.2 and 0.72 cases per million persons annually [ 1 , 3 ]. LGL leukemia is characterized by the clonal proliferation of large granular lymphocytes derived from either NK cells or T cells.…”

“…While NK cells function as components of innate immunity, T cells operate within the adaptive immune system, identifying specific antigens and mounting targeted immune responses. Within the realm of LGL leukemia, NK cell involvement may further manifest as a signal transducer and activator of transcription 3 (STAT3) mutated NK cell leukemia, presenting as an aggressive form with early systemic disease and organomegaly [ 2 , 3 ]. Conversely, T-cell leukemia, purportedly activated by specific antigen-receptor binding, presents as a more chronic and indolent variant.…”

“…Symptoms of T-cell leukemia vary from patient to patient with several of them developing hematological and autoimmune states. In a study done in 1994, the most common manifestations of T-cell LGL were constitutional, with 60% of patients expressing fatigue [ 3 ]. The most common hematological complication was neutropenia with 50% of patients diagnosed with absolute neutropenia, and 10-15% of patients reported at the time of diagnosis to have infections or a history of infections [ 3 ] as in the patient described in this report.…”

“…In a study done in 1994, the most common manifestations of T-cell LGL were constitutional, with 60% of patients expressing fatigue [ 3 ]. The most common hematological complication was neutropenia with 50% of patients diagnosed with absolute neutropenia, and 10-15% of patients reported at the time of diagnosis to have infections or a history of infections [ 3 ] as in the patient described in this report. However, several other autoimmune conditions were also found in patients.…”

“…In a study conducted in France, 23 of the patients who were observed to develop kidney injury were treated with corticosteroids and several lines of immunosuppressive regimens including cyclosporine, methotrexate, tumor necrosis factor alpha inhibitors, and leflunomide [ 5 ]. The association of T-cell LGL with several autoimmune diseases, including the diseases identified in the kidney, provided a reason for immunosuppression [ 3 ]. However, the result of immunosuppressive treatment led to no detection of clonality.…”