Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection (authors reply inN Engl J Med. 2005 May 12;352(19):2027-8)

BACKGROUND: Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients. METHODS: We studied 33 kidney-transplant recipients who had refractory vascular rejection. Thirteen had donor-specific anti-HLA antibodies, whereas 20 did not Malignant hypertension was present in 16 of the patients without anti-HLA antibodies, 4 of whom had seizures. The remaining 17 patients had no malignant hypertension. We hypothesized that activating antibodies targeting the angiotensin II type 1 (AT1) receptor might be involved. RESULTS: Activating IgG antibodies targeting the AT1 receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients. These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT1 receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT1-receptor-activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-κB. The AT1 antagonist losartan blocked agonistic AT1-receptor antibody-mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model. CONCLUSIONS: A non-HLA, AT1-receptor-mediated pathway may contribute to refractory vascular rejection, and affected patients might benefit from removal of AT 1-receptor antibodies or from pharmacologic blockade of AT 1 receptors

Combinatorial 3-manifolds with transitive cyclic symmetry

In this article we give combinatorial criteria to decide whether a transitive cyclic combinatorial d-manifold can be generalized to an infinite family of such complexes, together with an explicit construction in the case that such a family exists. In addition, we substantially extend the classification of combinatorial 3-manifolds with transitive cyclic symmetry up to 22 vertices. Finally, a combination of these results is used to describe new infinite families of transitive cyclic combinatorial manifolds and in particular a family of neighborly combinatorial lens spaces of infinitely many distinct topological types.Comment: 24 pages, 5 figures. Journal-ref: Discrete and Computational Geometry, 51(2):394-426, 201

Vascular Remodeling in Health and Disease

The term vascular remodeling is commonly used to define the structural changes in blood vessel geometry that occur in response to long-term physiologic alterations in blood flow or in response to vessel wall injury brought about by trauma or underlying cardiovascular diseases.1, 2, 3, 4 The process of remodeling, which begins as an adaptive response to long-term hemodynamic alterations such as elevated shear stress or increased intravascular pressure, may eventually become maladaptive, leading to impaired vascular function. The vascular endothelium, owing to its location lining the lumen of blood vessels, plays a pivotal role in regulation of all aspects of vascular function and homeostasis.5 Thus, not surprisingly, endothelial dysfunction has been recognized as the harbinger of all major cardiovascular diseases such as hypertension, atherosclerosis, and diabetes.6, 7, 8 The endothelium elaborates a variety of substances that influence vascular tone and protect the vessel wall against inflammatory cell adhesion, thrombus formation, and vascular cell proliferation.8, 9, 10 Among the primary biologic mediators emanating from the endothelium is nitric oxide (NO) and the arachidonic acid metabolite prostacyclin [prostaglandin I2 (PGI2)], which exert powerful vasodilatory, antiadhesive, and antiproliferative effects in the vessel wall

Covid-19, ACE2, and the kidney

We are confronted with the most dramatic pandemic world-wide for the past 100 years. We are armed "to-the-teeth" compared to 1918, we know the agent, the genomic sequence, the bodily entry, the proliferation rate, the damage pathogenesis, and the very nature of our enemy. We can identify its bodily presence and our resistance to it in terms of neutralizing antibody production. Nonetheless, the disease has laid lame the great nations of the current world and crippled the less fortunate countries. The primary disease features are not the kidney. However, the entry point has much to do with renal and cardiovascular disease. The kidney is a common target of corona-virus (SARS-CoV2) disease; the longer-term consequences could be as well