Reversal of proteinuric renal disease and the emerging role of endothelin

Proteinuria is a major long-term clinical consequence of diabetes and hypertension, conditions that lead to progressive loss of functional renal tissue and, ultimately, end-stage renal disease. Proteinuria is also a strong predictor of cardiovascular events. Convincing preclinical and clinical evidence exists that proteinuria and the underlying glomerulosclerosis are reversible processes. This Review outlines the mechanisms involved in the development of glomerulosclerosis-particularly those responsible for podocyte injury-with an emphasis on the potential capacity of endothelin receptor blockade to reverse this process. There is strong evidence that endothelin-1, a peptide with growth-promoting and vasoconstricting properties, has a central role in the pathogenesis of proteinuria and glomerulosclerosis, which is mediated via activation of the ET(A) receptor. Several antiproteinuric drugs, including angiotensin-converting-enzyme inhibitors, angiotensin receptor antagonists, statins and certain calcium channel blockers, inhibit the formation of endothelin-1. Preclinical studies have demonstrated that endothelin receptor antagonists can reverse proteinuric renal disease and glomerulosclerosis, and preliminary studies in humans with renal disease have shown that these drugs have remarkable antiproteinuric effects that are additive to those of standard antiproteinuric therapy. Additional clinical studies are needed

Sensitive Solid-Phase Detection of Donor-Specific Antibodies as an Aid Highly Relevant to Improving Allograft Outcomes

Transplant recipients who have had sensitizing events such as pregnancies, blood transfusions and previous transplants often develop antibodies directed against human leukocyte antigen (HLA)-molecules of the donor tissue. These pre-formed donor-specific antibodies (DSA) represent a high risk of organ failure as a consequence of antibody-mediated hyper-acute or acute allograft rejection. As a first assay to detect DSA, the complement-dependent lymphocytotoxicity assay (CDC) was established more than 40 years ago. However, this assay is characterized by several drawbacks such as a low sensitivity and a high susceptibility to various artificial factors generally not leading to valid and reliable outcomes under several circumstances that are reviewed in this article. Furthermore, only those antibodies that exert complement-fixing activity are detected. As a consequence, novel procedures that act independently of the complement system and that do not represent functional assays were generated in the format of solid phase assays (SPAs) (bead- or ELISA-based). In this article, we review the pros and cons of these sensitive SPA in comparison with the detection of DSA through the use of the traditional methods such as CDC and flow cytometric analyses. Potential drawbacks of the alternative methodological approaches comprising high background reactivity, susceptibility to environmental factors and the possible influence of subjective operators' errors concerning the interpretation of the results are summarized and critically discussed for each method. We provide a forecast on the future role of SPAs reliably excluding highly deleterious DSA, thus leading to an improved graft survival