RESUMO
Introduction: Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1ß (IL-1ß) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI. Methods: IL-1R1 was selectively depleted in CD11c+-expressing myeloid cells with CD11cCre + /IL-1R1 fl/fl (Myel KO) mice. Myel KO and littermate controls (CD11cCre - /IL-1R1 fl/fl-Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c+ bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice. Results: Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1ß) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/Il1rn), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1ß-induced tubular cell injury. Discussion: Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c+ myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.
RESUMO
OBJECTIVE: Limited data exist on the effect of rheumatoid arthritis (RA) on maternal postpartum outcomes. Using a real-world, electronic health record (EHR) cohort, we assessed maternal postpartum outcomes in RA. METHODS: In a large, de-identified EHR, we identified possible RA deliveries using ≥1 delivery ICD-9 or ICD-10-CM codes and a validated RA algorithm. RA cases were required to be diagnosed by a rheumatologist on chart review. Maternal postpartum outcomes included rates of blood transfusion, rates of infection up to 6 weeks postpartum defined by a clinician, and length of hospital stay. We also identified deliveries to women without autoimmune diseases. RESULTS: We identified 202 deliveries occurring after RA diagnosis and 596 deliveries to controls without autoimmune diseases. Postpartum infection rates were similar among RA patients and controls (8% vs. 4%, p = 0.10), as were red blood cell transfusion rates (2% vs. 2%, p = 1.00). RA case status was not significantly associated with postpartum infection (OR = 2.10, 95% CI 0.88 - 4.98, p = 0.09) but was significantly associated with preterm birth (OR = 2.11, 95% CI 1.38 - 3.23, p = 0.001). Corticosteroid use during pregnancy was common at 41%, while tumor necrosis factor inhibitor use was 13%. After adjusting for age at delivery and race, corticosteroid use at delivery was not associated with postpartum maternal infections but was associated with a significantly lower birthweight in RA cases. CONCLUSION: Women with RA have an increased risk of adverse pregnancy outcomes, particularly preterm birth. Our study highlights, however, that maternal postpartum outcomes such as postpartum infection and blood transfusion are not significantly increased in RA patients.
