Immunotolerance in liver transplantation: a primer for the clinician.

The use of immunosuppressive medications for solid organ transplantation is associated with cardiovascular, metabolic, and oncologic complications. On the other hand, the development of graft rejection is associated with increased mortality and graft dysfunction. Liver transplant recipients can withdraw from immunosuppression without developing graft injury while preserving an adequate antimicrobial response - a characteristic known as immunotolerance. Immunotolerance can be spontaneously or pharmacologically achieved. Contrary to the classic dogma, clinical studies have elucidated low rates of true spontaneous immunotolerance (no serologic or histological markers of immune injury) among liver transplant recipients. However, clinical, serologic, and tissue biomarkers can aid in selecting patients in whom immunosuppression can be safely withdrawn. For those who failed an immunosuppression withdrawal trial or are at high risk of rejection, pharmacological interventions for immunotolerance induction are under development. In this review, we provide an overview of the mechanisms of immunotolerance, the clinical studies investigating predictors and biomarkers of spontaneous immunotolerance, as well as the potential pharmacological interventions for inducing it.

COVID-19-Associated Glomerular Disease.

BACKGROUND: Studies have documented AKI with high-grade proteinuria in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In some patients, biopsies have revealed collapsing glomerulopathy, a distinct form of glomerular injury that has been associated with other viruses, including HIV. Previous patient reports have described patients of African ancestry who developed nephrotic-range proteinuria and AKI early in the course of disease. METHODS: In this patient series, we identified six patients with coronavirus disease 2019 (COVID-19), AKI, and nephrotic-range proteinuria. COVID-19 was diagnosed by a positive nasopharyngeal swab RT-PCR for SARS-CoV-2 infection. We examined biopsy specimens from one transplanted kidney and five native kidneys. Three of the six patients underwent genetic analysis of APOL1, the gene encoding the APOL1 protein, from DNA extracted from peripheral blood. In addition, we purified genomic DNA from paraffin-embedded tissue and performed APOL1 genotype analysis of one of the native biopsies and the donor kidney graft. RESULTS: All six patients were of recent African ancestry. They developed COVID-19-associated AKI with podocytopathy, collapsing glomerulopathy, or both. Patients exhibited generally mild respiratory symptoms, and no patient required ventilator support. Genetic testing performed in three patients confirmed high-risk APOL1 genotypes. One APOL1 high-risk patient developed collapsing glomerulopathy in the engrafted kidney, which was transplanted from a donor who carried a low-risk APOL1 genotype; this contradicts current models of APOL1-mediated kidney injury, and suggests that intrinsic renal expression of APOL1 may not be the driver of nephrotoxicity and specifically, of podocyte injury. CONCLUSIONS: Glomerular disease presenting as proteinuria with or without AKI is an important presentation of COVID-19 infection and may be associated with a high-risk APOL1 genotype.