Sphingosine Kinase-2 (Sphk2) is responsible for the production of the bioactive lipid Sphingosine-1 Phosphate, a key regulator of tissue repair. Here we address the in vivo significance of Sphingosine Kinase -2 in renal inflammation/fibrosis in response to unilateral ureteral obstruction using both genetic and pharmacological strategies. Obstructed kidneys of Sphk2-/- mice showed reduced renal damage and diminished levels of the renal injury markers TGFβ1 and αSMA when compared to wild type controls. We found a consistently significant increase in anti-inflammatory (M2) macrophages in obstructed Sphk2-/- kidneys by flow cytometry and a decrease in mRNA levels of the inflammatory cytokines, MCP1, TNFα, CXCL1 and ILβ1, suggesting an anti-inflammatory bias in the absence of Sphk2. Indeed, metabolic profiling showed that the pro-inflammatory glycolytic pathway is largely inactive in Sphk2-/- bone marrow-derived macrophages. Furthermore, treatment with the M2-promoting cytokines IL-4 or IL-13 demonstrated that macrophages lacking Sphk2 polarized more efficiently to the M2 phenotype than wild type cells. Bone marrow transplant studies indicated that expression of Sphk2-/- on either the hematopoietic or parenchymal cells did not fully rescue the pro-healing phenotype, confirming that both infiltrating M2-macrophages and the kidney microenvironment contribute to the damaging Sphk2 effects. Importantly, obstructed kidneys from mice treated with an Sphk2 inhibitor recapitulated findings in the genetic model. These results demonstrate that reducing Sphk2 activity by genetic or pharmacological manipulation markedly decreases inflammatory and fibrotic responses to obstruction, resulting in diminished renal injury and supporting Sphk2 as a novel driver of the pro-inflammatory macrophage phenotype.
This case report illustrates a tragic example of a "missed diagnosis" of amyloid light-chain (AL) amyloidosis with cardiac involvement that led to progressive heart failure and the ultimate death of the patient. It had a rather atypical presentation in terms of cardiac imaging, although there were certain highly suspicious clinical features, cardiac and otherwise. It also illustrates the importance of selecting the most appropriate assays to establish (or rule out) the presence of monoclonal immunoglobulin consistent with AL amyloidosis, which has a poor clinical prognosis, as unfortunately demonstrated in this case.
With the implementation of the new heart transplant (HT) allocation system, patients requiring biventricular support systems have the highest priority, a shorter waitlist time, and a higher frequency of HT. However, the short-term and long-term outcomes of such patients are often disputed. Hence, we examined the outcomes of these patients who underwent HT before change in allocation scheme. Additionally, we compared post-HT outcomes of extracorporeal membrane oxygenation (ECMO) with other nondischargeable biventricular (BiVAD) supported patients. We identified adult ECMO or BiVAD supported HT recipients between 2000 and 2018 in the Scientific Registry of Transplant Recipients database. We compared survival with the Kaplan-Meier method. Using overlap propensity score weighting, we constructed Cox proportional hazards regression models to determine the risk-adjusted influence of BiVAD versus ECMO on survival. Of the 730 patients HT recipients; 528 (72.3%) and 202 (27.7%) were bridged with BiVAD and ECMO, respectively. For BiVAD versus ECMO patients, the 30-day, 1-year, 3-year, and 5-year mortality rates were 8.0% versus 14.4%, 16.3% versus 21.3%, 22.4% versus 25.3%, and 26.3% versus 25.7%, respectively. Risk-adjusted post-HT survival of BiVAD and ECMO patients at 30-day (HR 1.24 [95% CI, 0.68–2.27]; P = 0.4863), 1-year (HR 1.29 [95% CI, 0.80–2.09]; P = 0.3009), 3-year (HR 1.27 [95% CI, 0.83–1.94]; P = 0.2801), and 5-year (HR 1.35, 95% CI, 0.90–2.05; P = 0.1501) were similar. Around three-fourth of the ECMO or BiVAD supported patients were alive at 5-years post-HT. The short-term and long-term post-HT survivals of groups were comparable.
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