Background: The COVID-19 pandemic has major implications on kidney transplant recipients (KTRs) since they show increased mortality due to impaired immune responses to SARS-CoV-2 infection and a reduced efficacy of SARS-CoV-2 vaccination. Surprisingly, dialysis patients have shown superior seroconversion rates after vaccination compared to KTRs. Therefore, we investigated peripheral blood B cell (BC) composition before and after kidney transplantation (KT) and aimed to screen the BC compartment to explain impaired antibody generation.Methods: A total of 105 patients were recruited, and multicolor flow cytometric phenotyping of peripheral venous blood BC subpopulations was performed before and 1 year after KT. Complete follow-up was available for 71 individuals. Anti-SARS-CoV-2 antibodies were collected retrospectively and were available for 40 subjects, who had received two doses of an mRNA-based vaccine (BNT162b2 or mRNA-1273).Results: Overall, relative BC frequencies within lymphocytes decreased, and their absolute counts trended in the same direction 1 year after KT as compared to CKD G5 patients. Frequencies and absolute numbers of naïve BCs remained stable. Frequencies of double negative BCs, a heterogeneous subpopulation of antigen experienced BCs lacking CD27 expression, were increased after KT, yet their absolute counts were similar at both time points. Transitional BCs (TrBCs) and plasmablasts were significantly reduced after KT in absolute and relative terms. Memory BCs were affected differently since class-switched and IgM-only subsets decreased after KT, but unswitched and IgD-only memory BCs remained unchanged. CD86⁺ and CD5⁺ expression on BCs was downregulated after KT. Correlational analysis revealed that TrBCs were the only subset to correlate with titer levels after SARS-CoV-2 vaccination. Responders showed higher TrBCs, both absolute and relative, than non-responders.Conclusion: Together, after 1 year, KTRs showed persistent and profound compositional changes within the BC compartment. Low TrBCs, 1 year after KT, may account for the low serological response to SARS-CoV-2 vaccination in KTRs compared to dialysis patients. Our findings need confirmation in further studies as they may guide vaccination strategies.

Selectively targeting the E-type prostanoid receptor 4 (EP4) might be a new therapeutic option in the treatment of glomerulonephritis (GN), since the EP4 receptor is expressed on different immune cells, resident kidney cells, and endothelial cells, which are all involved in the pathogenesis of immune-complex GN. This study aimed to evaluate the therapeutic potential and to understand the mode of action of EP4 agonist in immune-complex GN using the murine model of nephrotoxic serum nephritis (NTS). In vivo, NTS mice were treated two times daily with two different doses of an EP4 agonist ONO AE1-329 or vehicle for 14 days total. The effect of PGE2 and EP4 agonism and antagonism was tested on murine distal convoluted tubular epithelial cells (DCT) in vitro. In vivo, the higher dose of the EP4 agonist led to an improved NTS phenotype, including a reduced tubular injury score and reduced neutrophil gelatinase-associated lipocalin (NGAL) and blood urea nitrogen (BUN) levels. EP4 agonist treatment caused decreased CD4⁺ T cell infiltration into the kidney and increased proliferative capacity of tubular cells. Injection of the EP4 agonist resulted in dose-dependent vasodilation and hypotensive episodes. The low-dose EP4 agonist treatment resulted in less pronounced episodes of hypotension. In vitro, EP4 agonism resulted in cAMP production and increased distal convoluted tubular (DCT) proliferation. Taken together, EP4 agonism improved the NTS phenotype by various mechanisms, including reduced blood pressure, decreased CD4⁺ T cell infiltration, and a direct effect on tubular cells leading to increased proliferation probably by increasing cAMP levels.

Rapid progressive glomerulonephritis (GN) often leads to end-stage kidney disease, driving the need for renal replacement therapy and posing a global health burden. Low-dose cytokine-based immunotherapies provide a new strategy to treat GN. IL-15 is a strong candidate for the therapy of immune-mediated kidney disease since it has proven to be tubular-protective before. Therefore, we set out to test the potential of low-dose rIL-15 treatment in a mouse model of nephrotoxic serum nephritis (NTS), mimicking immune complex-driven GN in humans. A single low-dose treatment with rIL-15 ameliorated NTS, reflected by reduced albuminuria, less tissue scarring, fewer myeloid cells in the kidney, and improved tubular epithelial cell survival. In addition, CD8⁺ T cells, a primary target of IL-15, showed altered gene expression and function corresponding with less cytotoxicity mediated by rIL-15. With the use of transgenic knock-out mice, antibody depletion, and adoptive cell transfer studies, we here show that the beneficial effects of rIL-15 treatment in NTS depended on CD8⁺ T cells, suggesting a pivotal role for them in the underlying mechanism. Our findings add to existing evidence of the association of IL-15 with kidney health and imply a potential for low-dose rIL-15 immunotherapies in GN.

Key Points: Selective erythroid atypical chemokine receptor 1 deficiency exacerbated disease activity in experimental GN via changes of the myeloid lineage. Activated monocytes and profibrogenic phenotypes of macrophages underlaid the kidney phenotype observed in erythroid-silent individuals. Genetically modified mouse models showed pathomechanisms of kidney diseases in patients of West African ancestry with erythroid atypical chemokine receptor 1 deficiency. Background: Single-nucleotide polymorphisms of the atypical chemokine receptor 1 ( ACKR1 ) gene encode human Duffy antigen blood groups. Most individuals of West African ancestry carry a single-nucleotide polymorphism in the promoter region of the ACKR1 gene that disrupts its transcription in erythroid cells but not in venular endothelial cells, leading to an erythroid-silent, FyBES Duffy phenotype. Methods: We used two mouse models of erythroid-selective ACKR1 deficiency to delineate the fundamental role of this receptor in the erythroid compartment in regulating the development of experimental immune-mediated kidney disease. Results: Humanized transgenic Duffy erythroid-silent Duffy-negative transgene mice and chimeric wild-type mice transplanted with ACKR1-deficient bone marrow, both selectively lacking erythroid ACKR1, showed increased disease activity and fibrosis after induction of nephrotoxic serum nephritis, as compared with their respective controls. Mice lacking erythroid ACKR1 exhibited altered serum chemokine levels and bone marrow monocytes displaying activated and promigratory phenotypes. Moreover, they showed an increase in kidney-infiltrating macrophages that were characterized by a profibrotic transcriptome signature. No changes in ACKR1 expression in kidney vascular endothelial cells were seen in erythroid ACKR1-deficient mice with or without nephrotoxic serum nephritis. Conclusions: Our data demonstrates that erythroid-specific ACKR1 deficiency led to an increased infiltration of the kidney by macrophages with an altered profibrotic phenotype in nephrotoxic serum nephritis, resulting in aggravated kidney disease.