Kidney Adverse Events Associated with Immune Checkpoint Inhibitor Therapy: A Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND: The blockade of immune regulatory sites, CTLA-4, PD-1, and PD-L1 with Immune Checkpoint Inhibitors has revolutionized survival outcomes in cancer patients. However, immune checkpoint inhibitors are associated with a range of immune related adverse events. The aim of this network meta-analysis is to evaluate severe adverse kidney events in patients with oncological or hematological malignancy receiving monotherapy, dual therapy or combined therapy treatment with immune checkpoint inhibitors when compared to either placebo or standard chemotherapy. METHODS: Phase III Randomized Control Trials reporting severe grade (3-5) adverse kidney events were identified across five electronic databases from inception to May 2022. This was supplemented with hand searching of medical journals and the National Clinical Trials registry. A Bayesian network meta-analysis was performed for: acute kidney injury, hypertension, chronic kidney disease and the composite of all acute kidney adverse events. The results are reported as per PRISMA guidelines. RESULTS: 95 randomized control trials reported severe grade adverse kidney events. The risk of developing severe acute kidney injury is higher among patients who received PD-1 plus chemotherapy (OR 1.8 [95% CrI 1.4 to 2.5]) and PD-L1 plus chemotherapy (OR 1.80 [95% CrI 1.2 to 2.7]) compared to standard chemotherapy and placebo (94 studies, 63, 357 participants). The risk of developing the composite of all severe acute kidney adverse events is higher among patients who received PD-1 plus chemotherapy (OR 1.6 [95% CrI 1.1 to 2.3]) and PD-L1 plus chemotherapy (OR 1.7 [95% CrI 1.1 to 2.8) when compared to standard chemotherapy and placebo (95 studies, 63, 973 participants). CONCLUSIONS: The combined regimen of PD-1 + chemotherapy and PD-L1 + chemotherapy was associated with higher incidence of severe acute kidney injury and the composite of all severe acute kidney adverse events.

A case of minimal change disease during pregnancy - benefits of early diagnosis and use of corticosteroids.

Nephrotic syndrome presenting in pregnancy is rare and poses a diagnostic and therapeutic challenge. Timing of renal biopsy is important given the increased risk of bleeding and miscarriage, and the choice of immunosuppression is limited due to the teratogenicity profiles of standard drugs. We report and discuss a case of minimal change disease diagnosed by renal biopsy during early pregnancy and treated with corticosteroids throughout the pregnancy. Prompt diagnosis and treatment of glomerular disease in pregnancy are vital to prevent poor maternal and fetal outcomes.

Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody.

Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understood how the cells making them evade immune checkpoints. Here, single-cell multi-omics analysis demonstrates a shared mechanism with lymphoid malignancy in the formation of public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemic vasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptide sequencing and antibody synthesis, rare circulating B lymphocytes making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations. Lymphoma driver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)J mutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergo phase transition to insoluble aggregates at lower temperatures. These results reveal a pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutations leading to an iconic pathogenic autoantibody.

Saxagliptin reduces renal tubulointerstitial inflammation, hypertrophy and fibrosis in diabetes.

AIM: In addition to lowering blood glucose in patients with type 2 diabetes mellitus, dipeptidyl peptidase 4 (DPP4) inhibitors have been shown to be antifibrotic and anti-inflammatory. We have previously shown that DPP4 inhibition in human kidney proximal tubular cells exposed to high glucose reduced fibrotic and inflammatory markers. Hence, we wanted to demonstrate renoprotection in an in vivo model. METHODS: We used a type 1 diabetic animal model to explore the renoprotective potential of saxagliptin independent of glucose lowering. We induced diabetes in enos -/- mice using streptozotocin and matched glucose levels using insulin. Diabetic mice were treated with saxagliptin and outcomes compared with untreated diabetic mice. RESULTS: We provide novel data that saxagliptin limits renal hypertrophy, transforming growth factor beta-related fibrosis and NF-κBp65-mediated macrophage infiltration. Overall, there was a reduction in histological markers of tubulointerstitial fibrosis. There was no reduction in albuminuria or glomerulosclerosis. CONCLUSION: Our findings highlight the potential of DPP4 inhibition as additional therapy in addressing the multiple pathways to achieve renoprotection in diabetic nephropathy.

Empagliflozin for the treatment of Type 2 diabetes.

Diabetes and its complications account for a significant healthcare burden. There is increasing prevalence of diabetes and newer drugs are being investigated to improve outcomes. Sodium-glucose cotransporter inhibitors (SGLT2 inhibitors) are a newer class of medications, which prevent renal reabsorption of glucose and hence help in glycaemic control without significant risk of hypoglycaemia. Two drugs, namely dapagliflozin and canagliflozin have gained approval and empagliflozin is one of the advanced agents of this class. Early trials with empagliflozin have shown a stable pharmacokinetic profile and pharmacodynamic effects with significant SGLT2 selectivity. Clinical trials have shown improvement in glycaemic control and other benefits including weight loss and lowering of blood pressure. Ongoing trials and surveillance will provide answers about cardiovascular benefits, risk of osteoporosis and cancer.